The present invention relates to novel 4, 5, 6 and 7-indole and indoline derivatives which are potent serotonin reuptake inhibitors, pharmaceutical compositions containing these compounds and the use thereof for the treatment of disorders or diseases responsive to the inhibition of serotonin re-uptake. The compounds of the invention also possess antagonistic activity at 5-HT1A receptors and are considered to be particularly useful for the treatment of depression.
Selective serotonin (or 5-HT) reuptake inhibitors (SSRI""s) such as fluoxetine, paroxetine, sertraline, fluvoxamine and citalopram represent a major step forward in the treatment of depression because they have fewer and less severe side effects compared to first generation antidepressant (tricyclics and non-selective MAO inhibitors). The side effects associated with first generation antidepressants are such that they cause some patients to withdraw from treatment.
SSRI""s and all other antidepressants currently available suffer from a serious drawback in that several weeks of treatment is necessary to produce the therapeutic effect. The late onset of action is a significant problem, particularly in the treatment of patients with severe depression and suicide potential. Further, one in three patients are not responsive to SSRI""s.
Electrophysiological experiments in rats have shown that acute administration of SSRI""s reduces firing of 5-HT neurons of dorsal raphe nucleus in the rodent brain, whereas sustained treatment with SSRI""s leads to normalization of the firing activity of the 5-HT neurons (Arborelius, L. et al, Naunyn-Schmiedeberg ""s Arch. Pharmacol. 1995, 352, 157; Gartside, S. E. et al, Br. J. Pharmacol. 1995, 115, 1064; Chaput, Y. et al, Naunyn-Schmiedeberg ""s Arch. Pharmacol. 1986, 33, 342).
Further, it has been shown that the recovery of the firing activity of 5-HT neurons is linked to desensitization of somatodendritic 5-HT1A autoreceptors (Le Poul, E. et al, Naunyn-Schmiedeberg""s Arch. Pharmacol. 1995, 352, 141; Invemizzi, R. et al, Eur. J. Pharmacol. 1994, 260, 243).
It has thus been suggested that simultaneous administration of SSRJ""s and an agent causing rapid desensitization or inhibition of the 5-HT1A receptor mediated feed back mechanism would lead to rapid onset of antidepressive effect (Artigas, F. et al, Trends Neurosci. 1996, 19, 378; De Vry, J., et al, Drug News Perspec. 1996, 9, 270).
The effect of combined administration of a compound that inhibits serotonin reuptake and a 5-HT1A receptor antagonist has been evaluated in several studies (Innis, R. B. et al., Eur. J. Pharmacol., 1987, 143, p 195-204 and Gartside, S. E., Br. J. Phannacol. 1995, 115, p 1064-1070, Blier, P. et al, Trends Pharmacol. Sci. 1994, 15, 220). In these studies it was found that 5-HT1A receptor antagonists inhibit the decrease in firing caused by acute administration of serotonin reuptake inhibitors.
Further, treatment with a combination of pindolol (a well known 5-HT1A receptor and xcex2-adrenoceptor antagonist) and SSRI""s has been evaluated in clinical trials. A remarkable improvement of the mood of patients was reported within one week. In addition, combined administration of pindolol and a SSRI was shown to have a good effect on patients who were non-responsive to treatment with currently available antidepressants (Artigas F. et al., Arch. Gen. Psychiatry, 1994, 51, p 248-251 and Blier, P. et al., J. Clin. Psychopharmacol. 1995, 15, p 217-222).
Several patent applications have been filed which cover the use of a combination of a 5-HT1A antagonist and a serotonin reuptake inhibitor for the treatment of depression (see EP-A2-687 472 and EP-A2-714 663).
DE patent application No. 4414113 discloses certain 4-(indol-3-yl)-1-(indol-3-yl-alkylene)-piperidines having the general formula 
wherein n is 2-6 and the other substituents are as defined in the application. The compounds herein are claimed to have serotonin antagonistic and agonistic activities and to have effect on DOPA-accumulation in striatum and 5-HTP accumulation in N. Raphe. No biological data are given.
WO patent publication No. 94/21626 discloses compounds having the general formula 
wherein R2 is heteroaryl and the other substituents are as defined in the application. A compound wherein R2 is 5-indolyl which is structurally closely related to the compounds of the invention is specifically mentioned herein. No data are given. The compounds are only said to give Ki values of less than 1.5 xcexcM in a test for displacement of 3H spiperone from human dopamine D4 receptor subtypes in clonal cell lines. WO patent publication No. 94/21627 and No. 94/21630 relate to similar compounds having affinity for human dopamine D4 receptors.
WO patent publication No. 95/33721 relates to 1-(indanemethyl, dihydrobenzo-furanylmethyl, dihydrobenzothiophenylmethyl)piperidine,tetrahydro-pyridine, or piperazine derivatives having the general formula 
wherein one of X and Y is CH2 and the other is selected from the group consisting of CH2, O, or S, Ar is aryl or heteroaryl, e.g. 1-, 2-, or 3-indolyl and the other substituents is as defined in the application. The compounds interact with central 5-HT receptors, in particular with 5-HT1A and 5-HT2A receptors. Some of the compounds are said to have 5-HT reuptake inhibiting effect.
It is the object of the present invention to provide compounds with potent serotonin reuptake inhibiting activity as well as antagonistic properties at 5-HT1A receptors. Such compounds may be useful as fast onset of action medicaments for the treatment of affective disorders, such as depression.
A further object of the present invention is to provide a pharmaceutical composition comprising these compounds as active ingredients.
The invention then, inter alia, comprises the following alone or in combination:
A substituted 4-, 5-, 6-, or 7-indole or indoline derivative of formula (I) 
wherein W is N, C, CH or COH and the dotted lines indicate optional bonds and
wherein A is a group having the formula 
wherein X is CR1A, CHR1A, N, NR1B, O, or S, where R1A is as defined for R3 to R9 below, and where R1B is as defined for R10 below;
Y is CR2A, CHR2A, N, NR2B, O, or S, where R2A is as defined for R3 to R9 below and where R2B is as defined for R10 below, and
the dotted lines indicate optional bonds;
provided that X and Y are not both O or S;
A is a group having the formula 
wherein
xe2x80x83X is CR1A, CHR1A, N, NR1B, O, or S, where R1A is as defined for R3 to R9 below, and where R1B is as defined for R10 below;
U is C, CH, orN; and
the dotted lines indicate optional bonds;
A is a group having the formula 
wherein
U is C, CH, or N;
Y is CR2A, CHR2A, N, NR2B, O, or S, where R2A is as defined for R3 to R9 below and where R2B is as defined for R10 below;
and the dotted lines indicate optional bonds;
n is 0, 1, 2, 3, 4, or 5, and m is 0, 1, 2, 3, 4, or 5;
Z is CH2, O, S, CO, SO, or SO2, provided that if n is 0 then Z is CH2;
R3-R9 and R11 to R12 are independently selected from hydrogen, halogen, cyano, nitro, C1-6-alk(en/yn)yl, C1-6 alkoxy, C1-6-alkylthio, hydroxy, hydroxy-C1-6-alkyl, C1-6-alkoxycarbonyl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, C1-6-alkylcarbonyl, phenylcarbonyl, halogen substituted phenylcarbonyl, trifluoromethyl, trifluoromethylsulfonyloxy, C1-6 alkylsulfonyl, aryl and heteroaryl, and/or two adjacent groups taken from R3-R9 may together form a methylenedioxy group,
and/or two adjacent groups R7-R9 may together form a cyclopentyl or cyclohexyl ring which may be substituted with one or more methyl groups,
and/or one of R3-R9 may alternatively be a group xe2x80x94NR13R14 wherein R13 is as defined for R10 below and R14 is hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6 alk(en/yn)yl, aryl, heteroaryl, aryl-C1-6 alkyl, or heteroaryl-C1-6-alkyl;
R10 is
hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6 alk(en/yn)yl, aryl, heteroaryl, aryl-C1-6-alkyl, heteroaryl-C1-6-alkyl, acyl, thioacyl, C1-6-alkylsulfonyl, trifluoromethylsulfonyl, arylsulfoniyl, or heteroarylsulfonyl;
R15VCOxe2x80x94 wherein V is O or S and R15 is C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, aryl, or heteroaryl; or
a group R16R17NCOxe2x80x94 or R16R17NCSxe2x80x94 wherein R16 and R17 are independently selected from hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, heteroaryl, or aryl, or R16 and R17 together with the N-atom to which they are linked, form a pyrrolidinyl, piperidinyl, morpholinyl, or perhydroazepin group;
or an acid addition salt thereof.
In a particular embodiment, the compounds of the invention are compounds wherein A is a group of formula (IIA) including such compounds wherein A is a group having the formulas illustrated below: 
wherein R3to R6 and the dotted lines are as defined above.
In a particular embodiment A is a group having the formula 
wherein R3 to R6 and the dotted lines are as defined above.
In another particular embodiment the present invention relates to compounds having the formula 
wherein R7 to R12, W, A, Z, n, m and the dotted lines are as defined above.
In a particular embodiment Z is CH2 and n+m is 0, 1, 2, 3, 4, 5, or 6.
In another embodiment the present invention relates to compounds having the formula II above and A is a group having the formula IIA above.
In another particular embodiment the present invention relates to compounds having the formula II above and A is a group having the formula 
wherein R3 to R6 and the dotted lines are as defined above.
In a further particular embodiment the present invention relates to compounds having the formula II above and A is a group having the formula 
wherein R3 to R6 and the dotted lines are as defined above.
In a particular embodiment the compounds of the invention are the compounds wherein R3-R9 and R11-R12 is hydrogen, halogen, cyano, nitro, C1-6-alkyl, C1-6-alkoxy hydroxy, hydroxy-C1-6-alkyl, C1-6-alkoxycarbonyl and trifluoromethyl; and R10 is hydrogen.
In another particular embodiment of the invention, W is N.
Examples of compounds according to the invention are the compounds
1-(2-(3-Benzofuranyl)ethyl)-4-(1H-indol-4-yl)piperazine,
1-(3-Benzofuranylmethyl)-4-(1H-indol-4-yl)piperazine,
1-(2-(5-Fluoro-3-benzofuranyl)ethyl)-4-(1H-indol-4-yl)piperazine,
1-(4-(5-Fluoro-3-benzofuranyl)-1-butyl)-4-(1H-indol-4-yl)piperazine,
1-(2-(1H-Indol-3-yl)ethyl)-4-(1H-indol-4-yl)piperazine,
1-(3-(1H-Indol-3-yl)-1-propyl)-4-(1H-indol-4-yl)piperazine,
1-(4-(1H-Indol-3-yl)-1-butyl)-4-(1H-indol-4-yl)piperazine,
1-(3-(5-Fluoro-3-benzofuranyl)-1-propyl)-4-(1H-indol-4-yl)piperazine,
1-(2-(2-Methyl-4,5,6,7-tetrafluoro-3-benzofuranyl)ethyl)-4-(1H-indol-4-yl)piperazine,
1-(2-(3-Indazolyl)ethyl)-4-(1H-indol-4-yl)piperazine,
1-(2-(6-Chloro-3-indazolyl)ethyl)-4-(1H-indol-4-yl)piperazine,
1-(2-(7-Cyano-1H-indol-3-yl)ethyl)-4-(1H-indol-4-yl)piperazine,
1-(2-(6-Chloro-1H-indol-3-yl)ethyl)-4-(1H-indol-4-yl)piperazine,
1-(2-(4-Chloro-1H-indol-3-yl)ethyl)-4-(1H-indol-4-yl)piperazine,
1-(2-(5-Fluoro-1H-indol-3-yl)ethyl)-4-(1H-indol-4-yl)piperazine,
1-(2-(6-Chloro-1H-indol-3-yl)ethyl)-4-(1H-indol-4-yl)-1,2,3,6-tetrahydropyridine,
1-(2-(5-Fluoro-1H-indol-3-yl)ethyl)-4-(1H-indol-4-yl)-1,2,3,6-tetrahydropyridine,
1-(2-(7-Bromo-1H-indol-3-yl)ethyl)-4-(1H-indol-4-yl)piperazine,
1-(1-Allyl-1H-indol-4-yl)-4-(2-(6-chloro-1H-indol-3-yl)ethyl)piperazine,
1-(1-Allyl-1H-indol-4-yl)-4-(2-(5-fluoro-1H-indol-3-yl)ethyl)piperazine,
1-(1-Benzyl-1H-indol-4-yl)-4-(2-(6-chloro-1H-indol-3-yl)ethyl)piperazine,
1-(1-Benzyl-1H-indol-4-yl)-4-(2-(5-fluoro-1H-indol-3-yl)ethyl)piperazine,
1-(1-Benzyl-1H-indol-4-yl)-4-(2-(5-bromo-1H-indol-3-yl)ethyl)piperazine,
1-(2-(6-Chloro-1H-indol-3-yl)ethyl)-4-(1-propargyl-1H-indol-4-yl)piperazine,
1-(2-(1H-Indol-3-yl)ethyl)-4-(1-propargyl-1H-indol-4-yl)piperazine,
1-(2-(5-Fluoro-1H-indol-3-yl)ethyl)-4-(1-propargyl-1H-indol-4-yl)piperazine,
1-(2-(5-Bromo-1H-indol-3-yl)ethyl)-4-(1-propargyl-1H-indol-4-yl)piperazine,
1-(1-Benzyl-1H-indol-4-yl)-4-(2-(1-indol-3-yl)ethyl)piperazine,
1-(2-(5-Bromo-1H-indol-3-yl)ethyl)-4-(1H-indol-5-yl)piperazine,
1-(2-(5-Chloro-1H-indol-3-yl)ethyl-(1H-indol-5-yl)piperazine,
1-(2-(5-Fluoro-1H-indol-3-yl)ethyl)-4-(6-hydroxymethyl-1H-indol-4-yl)piperazine,
1-(2-(6-Chloro-1H-indol-3-yl)ethyl)-4-(6-hydroxymethyl-1H-indol-4-yl)piperazine,
1-(2-(5-Bromo-1H-indol-3-yl)ethyl)-4-(6-hydroxymethyl-1H-indol-4-yl)piperazine,
1-(3-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-propyl)-4-(1H-indol-4-yl)piperazine,
1-(2-(1H-Indol-3-yl)ethyl)-4-(6-methoxycarbonyl-1H-indol-4-yl)piperazine,
1-(2-(6-Chloro-1H-indol-3-yl)ethyl)-4-(6-methoxycarbonyl-1H-indol-4-yl)piperazine,
1-(2-(5-Fluoro-3-benzofuranyl)ethyl)-4-(6-methoxycarbonyl-1H-indol-4-yl)piperazine,
1-(5-Fluoro-3-benzofuranylmethyl)-4-(1H-indol-4-yl)piperazine,
1-(3-Cyano-1H-indol-4-yl)-4-(2-(1H-indol-3-yl)ethyl)piperazine,
1-(3-Cyano-1H-indol-4-yl)-4-(2-(5-fluoro-3-benzofuranyl)ethyl)piperazine,
1-(2-(6-Chloro-1H-indol-3-yl)ethyl)-4-(3-cyano-1H-indol-4-yl)piperazine,
1-(2-(3-Benzofuranyl)ethyl)-4-(3-cyano-1H-indol-4-yl)piperazine,
1-(1H-Indol-4-yl)-4-(2-(5-methyl-3-benzofuranyl)ethyl)piperazine,
1-(1H-Indol-4-yl)-4-(2-(4-methyl-3-benzofuranyl)ethyl)piperazine,
1-(3-(5-Fluoro-3-benzofuranyl)-1-propyl)-4-(1H-indol-4-yl)-1,2,3,6-tetrahydropyridine,
1-(2-(5-Chloro-3-benzofuranyl)ethyl)-4-(1H-indol-4-yl)piperazine,
1-(1H-Indol-4-yl)-4-(2-(6-methyl-3-benzofuranyl)ethyl)piperazine,
1-(2-(7-Chloro-3-benzofuranyl)ethyl)-4-(1H-indol-4-yl)piperazine,
1-(2-(4-Chloro-1H-indol-3-yl)ethyl)-4-(3-cyano-1H-indol-4-yl)piperazine,
1-(2-(6-Chloro-1H-indol-3-yl)ethyl-4-(1H-indol-4-yl)piperidine,
1-(2-(5-Chloro-1H-indol-3-yl)ethyl)-4-(1H-indol-4-yl)piperazine,
1-(2-(7-Bromo-1H-indol-3-yl)ethyl)-4-(1H-indol-4-yl)piperazine,
1-(2-(4-Chloro-1H-indol-3-yl)ethyl)-4-(1H-indol-4-yl)piperazine,
1-(2-(6-Trifluoromethyl-1H-indol-3-yl)ethyl)-4-(1H-indol-4-yl)piperazine,
1-(1H-Indol-4-yl)-4-(2-(5-methyl-1H-indol-3-yl)ethyl)piperazine,
1-(1H-Indol-4-yl)-4-(2-(6-methyl-1H-indol-3-yl)ethyl)piperazine,
1-(1H-Indol-4-yl)-4-(2-(7-methyl-1H-indol-3-yl)ethyl)piperazine,
1-(2-(4,5-Dichloro-3-benzofuranyl)ethyl)-4-(1H-indol-4-yl)piperazine,
1-(2-(5-Bromo-3-benzofuranyl)ethyl)-4-(1H-indol-4-yl)piperazine,
1-(2-(4-Chloro-1H-indol-3-yl)ethyl)-4-(1H-indol-4-yl)piperidine,
4-(1H-Indol-4-yl)-1-(2-(5-methyl-1H-indol-3-yl)ethyl)piperidine,
4-(1H-Indol-4-yl)-1-(2-(1H-indol-3-yl)ethyl)piperidine,
1-(1H-Indol-4-yl)-4-(3-(4-methyl-3-benzofuranyl)-1-propyl)piperazine,
4-(1H-Indol-4-yl)-1-(3-(4-methyl-3-benzofuranyl)-1-propyl)piperidine,
1-(3-(4-Chloro-3-benzofuranyl)-1-propyl)-4-(1H-indol-4-yl)piperazine,
1-(2-(6-Chloro-1H-indol-3-yl)ethyl)-4-(6-chloro-1H-indol-4-yl)piperazine,
1-(2-(6-Chloro-1H-indol-3-yl)ethyl)-4-(6-fluoro-1H-indol-4-yl)piperazine,
1-(2-(6-Chloro-1H-indol-3-yl)ethyl)-4-(6-cyano-1H-indol-4-yl)piperazine,
1-(2-(6-Chloro-1H-indol-3-yl)ethyl)-4-(7-chloro-1H-indol-4-yl)piperazine,
1-(2-(6-Chloro-1H-indol-3-yl)ethyl)-4-(7-cyano-1H-indol-4-yl)piperazine,
1-(2-(6-Chloro-1H-indol-3-yl)ethyl)-4-(2-cyano-1H-indol-4-yl)piperazine,
1-(2-(6-Chloro-1H-indol-3-yl)ethyl)-4-(1H-indolin-4-yl)piperazine,
1-(2-(6-Chloro-1H-indol-3-yl)ethyl)-4-(1H-indol-6-yl)piperazine and
1-(2-(6-Chloro-1H-indol-3-yl)ethyl)-4-(1H-indol-7-yl)piperazine,
or an acid addition salt thereof.
The invention also relates to a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable acid addition salt thereof and at least one pharmaceutically acceptable carrier or diluent.
In another aspect the invention relates to the use of a compound of the invention or a pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament for the treatment of a disorder or disease responsive to the inhibition of serotonin reuptake and antagonism of 5-HT1A receptors.
In a final object, the present invention relates to a method for the treatment of a disorder or disease of living animal body, including a human, which is responsive to the inhibition of serotonin reuptake and antagonism of 5-HT1A receptors comprising administering to such a living animal body, including a human, a therapeutically effective amount of a compound as above or a pharmaceutically acceptable acid addition salt thereof.
Diseases or disorders responsive to the inhibition of serotonin re-uptake and antagonistic activity at 5-HT1A receptors include affective disorders, such as depression, psychosis, anxiety disorders including general anxiety disorder and panic disorder and obsessive compulsive disorder.
Due to their combined antagonism of 5-HT1A receptors and serotonin reuptake inhibiting effect, the compounds of the invention are particularly useful as fast onset of action medicaments for the treatment of depression. The compounds may also be useful for the treatment of depression in patients who are resistant to treatment with currently available antidepressants.
In the groups of formula (IIA), (IIB) and (IIC), the presence and position of double bonds in the ring containing X, U and Y depend on the meaning of X, U and Y.
Thus, as regards the group of formula (IIA), it is very clear to a person skilled in the art, that when a dotted line emanating from X is a bond, then X is N or CR1A, and when the dotted line is not a bond then X is CHR1A, NR1B, O, or S; and when a dotted line emanating from Y is a bond, then Y is N, or CR1B and when the dotted line is not a bond Y is CHR2A, NR2B, O, or S.
Further, as regards the group of formula (IIB), it is very clear to a person skilled in the art, that when a dotted line emanating from X is a bond then X is N, or CR1A and when the dotted line is not a bond then X is CH1A, NR1B, O, or S; and when a dotted line emanating from U is a bond then U is C and when the dotted line is not a bond U is CH, or N.
And finally as regards the group of formula (IIC), it is very clear to a person skilled in the art that when a dotted line emanating from U is a bond then U is C and when the dotted line is not a bond U is CH, or N; and when a dotted line emanating from Y is a bond then Y is N, or CR2A and when the dotted line is not a bond then Y is CHR2A, NR2B, O, or S.
The same applies to W, which is N, CH, or COH when the dotted line emanating from W does not indicate a bond and C when it indicates a bond.
The expression C1-6-alk(en/yn)yl means a C1-6-alkyl, C2-6-alkenyl, or a C2-6-alkynyl group. The expression C3-8-cycloalk(en)yl means a C3-8-cycloalkyl- or cycloalkenyl group.
The term C1-6 alkyl refers to a branched or unbranched alkyl group having from one to six carbon atoms inclusive, including but not limited to methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl and 2-methyl-1-propyl.
Similarly, C2-6 alkenyl and C2-6 alkynyl, respectively, designate such groups having from two to six carbon atoms, including one double bond and one triple bond respectively, including but not limited to ethenyl, propenyl, butenyl, ethynyl, propynyl, and butynyl.
The terms C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylsulfonyl, C1-6 alkylamino, C1-6 alkylcarbonyl, hydroxy-C1-6-alkyl etc. designate such groups in which the C1-6 alkyl is as defined above.
The term C3-8 cycloalkyl designates a monocyclic or bicyclic carbocycle having three to eight C-atoms, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, etc.
The term C3-8 cycloalkenyl designates a monocyclic or bicyclic carbocycle having three to eight C-atoms and including one double bond.
In the term C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl and C1-6-alk(en/yn)yl are as defined above.
The term aryl refers to a carbocyclic aromatic group, such as phenyl, naphthyl, in particular phenyl. As used herein aryl may be substituted one or more times with halogen, nitro, cyano, trifluoromethyl, C1-6-alkyl, hydroxy and C1-6-alkoxy.
The term heteroaryl refers to a mono- or bicyclic heterocyclic group such as indolyl, thienyl, pyrimidyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, benzofuiranyl, benzothienyl, pyridyl and furanyl, in particular pyrimidyl, indolyl, and thienyl.
As used herein heteroaryl may be substituted one or more times with halogen, nitro, cyano, trifluoromethyl, C1-6-alkyl, hydroxy and C1-6-alkoxy.
In aryl-C1-6-alkyl and heteroaryl-C1-6-alkyl, aryl, heteroaryl and C1-6-alkyl is as defined above.
Halogen means fluoro, chloro, bromo or iodo.
As used herein the term acyl refers to formyl, C1-6-alk(en/yn)ylcarbonyl, arylcarbonyl, aryl-C1-6-alk(en/yn)ylcarbonyl, C3-8-cycloalk(en)ylcarbonyl, or a C3-8-cycloalk(en)yl-C1-6alk(en/yn)yl-carbonyl group and the term thioacyl is as the corresponding acyl group in which the carbonyl group is replaced with a thiocarbonyl group.
The acid addition salts of the invention are preferably pharmaceutically acceptable salts of the compounds of the invention formed with non-toxic acids. Exemplary of such organic salts are those with maleic, fiunaric, benzoic, ascorbic, succinic, oxalic, bis-methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, and theophylline acetic acids, as well as the 8-halotheophyllines, for example 8-bromotheophylline. Exemplary of such inorganic salts are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric acids.
Further, the compounds of this invention may exist in unsolvated as well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of this invention.
Some of the compounds of the present invention contain chiral centres and such compounds exist in the form of isomers (i.e. enantiomers). The invention includes all such isomers and any mixtures thereof including racemic mixtures.
Racemic forms can be resolved into the optical antipodes by known methods, for example, by separation of diastereomeric salts thereof with an optically active acid, and liberating the optically active amine compound by treatment with a base. Another method for resolving racemates into the optical antipodes is based upon chromatography on an optically active matrix. Racemic compounds of the present invention can also be resolved into their optical antipodes, e.g., by fractional crystallization of d- or 1-(tartrates, mandelates, or camphorsulphonate) salts for example. The compounds of the present invention may also be resolved by the formation of diastereomeric derivatives.
Additional methods for the resolution of optical isomers, known to those skilled in the art, may be used. Such methods include those discussed by J. Jaques, A. Collet, and S. Wilen in xe2x80x9cEnantiomers, Racemates, and Resolutionsxe2x80x9d, John Wiley and Sons, New York (1981).
Optically active compounds can also be prepared from optically active starting materials.
Finally, formula (I) includes any tautomeric forms of the compounds of the invention.
The compounds of the invention can be prepared by one of the following methods comprising:
a) reducing the carbonyl groups of a compound of formula (III) 
xe2x80x83wherein R3-R12, W and the dotted lines are as defined above;
b) alkylating an amine of formula (IV) 
xe2x80x83wherein R7-R12, W and the dotted lines are as defined above with a reagent of formula (V)
Gxe2x80x94(CH2)nxe2x80x94Zxe2x80x94(CH2)mxe2x80x94Axe2x80x83xe2x80x83(V)
wherein A, Z, n, and m are as defined above and G is a suitable leaving group such as halogen, mesylate, or tosylate;
c) reductive alkylation of an amine of formula 
xe2x80x83wherein R7-R12, W and the dotted lines are as defined above with a reagent of formula (VI)
Exe2x80x94(CH2)nxe2x80x94Zxe2x80x94(CH2)mxe2x80x94Axe2x80x83xe2x80x83(VI)
wherein A, Z, n and m are as defined above and E is either an aldehyde or a carboxylic acid group;
d) reducing the double bond of the indole ring, which is attached to the cyclic amine moiety, of formula (I) in order to obtain the corresponding 2,3-dihydroindole derivatives;
e) reducing the double bond of a tetrahydropyridine of formula (VII) 
xe2x80x83wherein R17-R12, A, Z, n, m, and the dotted lines are as previously defmed, on order to obtain the corresponding piperidine derivatives;
f) reducing the amide group of a compound of formula (VIII) 
xe2x80x83wherein R7-R12, A, W, Z, n, m, and the dotted lines are as previously defined;
g) reductive removal of one or more of the halogen substitutents R3-R9 and R11-R12 in a compound of formula (I) in which one or more of these substituents are selected from chloro, bromo, or iodo;
h) dialkylating an amine of formula (IX) 
xe2x80x83wherein R7-R12 and the dotted line are as defined above with a reagent of formula (X) 
wherein A, Z, n, and m are as defined above and G is a suitable leaving group such as halogen, mesylate, or tosylate;
i) dialkylating an amine of formula (XI)
H2Nxe2x80x94(CH2)nxe2x80x94Zxe2x80x94(CH2)mxe2x80x94Axe2x80x83xe2x80x83(XI)
xe2x80x83wherein A, Z, n, and m are as defined above with a reagent of formula (XII) 
wherein R7-R12, W, and the dotted line are as defined above and G is a suitable leaving group such as halogen, mesylate, or tosylate;
j) alkylating, arylating, or acylating one or both indole nitrogen atoms of a compound of formula (I) in which R10 is hydrogen, and/or X and/or Y is NH; or
k) reducing a compound of formula (I) in which R7, R8, or R9 is an alkoxycarbonyl group in order to obtain the corresponding hydroxymethyl group;
whereupon the compounds of formula (I) are isolated as the free base or in the form of an acid addition salt thereof.
The reduction according to method a) is preferably carried out in an inert organic solvent such as diethyl ether or tetrahydrofuran in the presence of lithium aluminium hydride at reflux temperature. Starting compounds of formula (TII) are generally prepared by condensation of 3-chlorooxalyl indoles (prepared as described in Houben-Weyl, Methoden der Organischen Chemie, Vol E6B2, p. 1058) with amines of formula (IV) in the presence of a base such as triethylamine or potassium carbonate.
The alkylation according to method b) is conveniently performed in a inert organic solvent such as a suitably boiling alcohol or ketone, preferably in the presence of an organic or inorganic base (potassium carbonate or triethylamine) at reflux temperature.
Indolylpiperazine derivatives of formula (IV) are conveniently prepared from the corresponding arylamine according to the method described by Martin et al, J. Med. Chem. 32 (1989) 1052, or the method described by Kruse et al, Rec. Trav. Chim. Pays-Bas 107 (1988) 303. The starting arylamines are either commercially available or are well-described in the literature.
Indolyl tetrahydropyridine derivatives of formula (IV) are known from literature (see eg. French Pat. 2458549). Conveniently, 1-protected 4, 5, 6, or 7-bromoindole is lithiated with BuLi followed by addition of 1-protected 4-piperidone and subsequent dehydration as outlined in an example below. The starting bromoindoles are either commercially available or well-described in the literature. Reagents of formula (V) are either commercially available or can be prepared by literature methods, eg. from the corresponding carboxylic acid derivative by reduction to the corresponding hydroxy derivatives and subsequent conversion of the hydroxy group to the group G by conventional methods.
The reductive alkylation according to method c) is performed by standard literature methods. The reaction can be performed in two steps, ie. coupling of derivatives of formula (IV) and the reagent of formula (VI) by standard methods via the carboxylic acid chloride or by use of coupling reagents such as eg. dicyclohexyl carbodiimide followed by reduction of the resulting amide with lithium aluminium hydride or alane. The reaction can also be performed by a standard one-pot procedure. Carboxylic acids or aldehydes of formula (VI) are either commercially available or described in the literature.
Reduction of the indole double bond according to method d) is conveniently performed by treatment with diborane or a diborane precursor such as the trimethylamine or dimethylsulfide complex in an inert solvent such as eg. tetrahydrofaran or dioxane from 0xc2x0 C. to reflux temperature followed by acid catalyzed hydrolysis of the intermediate borane derivative. The reduction can alternatively be performed by treatment with sodium cyanoborohydride in trifluoroacetic acid.
Reduction of the double bonds according to method e) is most conveniently performed by hydrogenation in an alcohol in the presence of a noble metal catalyst, such as eg. platinum or palladium.
Reduction of amide groups according to method f) is most conveniently performed with lithium aluminium hydride or alane in an inert organic solvent such as eg. tetrahydrofaran or diethylether from 0xc2x0 C. to reflux temperature.
The removal of halogen substituents according to method g) is conveniently performed by catalytic hydrogenation in an alcohol in the presence of a palladium catalyst or by treatment with ammomium formate in an alcohol at elevated temperatures in the presence of a palladium catalyst.
The dialkylation of amines according to methods h) and i) is most conveniently performed at elevated temperatures in an inert solvent such as eg. chlorobenzene, toluene, N-methylpyirolidinone, dimethylformamide, or acetonitrile. The reaction might be performed in the presence of base such as eg. potassium carbonate or triethylamine. Starting material for processes h) and i) are commercially available or can be prepared using conventional methods.
The indole N-alkylation or N-acylation are performed in an inert solvent such as eg. an alcohol or ketone at elevated temperatures in the presence of base, eg. potassium carbonate or triethylamine. Alternatively, a phase-transfer reagent can be used. The corresponding N-arylation is best performed under Ullmann-conditions as described in the literature.
The reduction of alkoxycarbonyl groups according to method k) is most conveniently performed with lithium aluminium hydride or alane in an inert organic solvent such as e.g. tetrahydrofuran.
The following examples will illustrate the invention further. They are, however, not to be construed as limiting.